Intravenous immunoglobulin in primary and secondary chronic progressive multiple sclerosis: a randomized placebo controlled multicentre study.

In patients with relapsing-remitting multiple sclerosis (MS), IVIG was shown to reduce the relapse rate and progression of disability. In patients with chronic progressive MS, a beneficial effect of IVIG was not documented in placebo controlled studies. This trial investigated the influence of IVIG in primary (PPMS) and secondary (SPMS) chronic progressive MS. Two-hundred and thirty-one patients stratified for PPMS (n=34) and SPMS (n=197) were randomly assigned to IVIG 0.4 g/kg per month or to placebo for 24 months. Primary endpoints were 1) the time to sustained progression of disease identified as worsening of the expanded disability status scale (EDSS) sustained for 3 months, and 2) the improvement of neurological functions defined by a patient's best EDSS score. Secondary endpoints were the proportion of patients with sustained progression, the relapse rate, the assessment of fine motor skills, visual evoked potentials, contrast sensitivity, depression and quality of life. Analysis of the intention-to-treat (ITT) population of combined PPMS and SPMS patients showed that the mean time to sustained progression was 74 weeks in the IVIG compared with 62 weeks in the placebo group (P=0.0406). When PPMS and SPMS patients were analysed separately, the time to sustained progression was also longer in the IVIG group, but the difference was not significant. There was no IVIG-mediated improvement in neurological functions. In the combined per protocol (PP) treated patients, IVIG treatment prolonged time to sustained progression by 13 weeks (P=0.0396). PPMS patients, but not SPMS patients showed a slight favourable IVIG effect on the best EDSS score. In the combined ITT population there were less patients with sustained progression in the IVIG than in the placebo group (P=0.028). The difference was significant in PPMS (P=0.016), but not in SPMS patients. In the combined PP population, there was a trend for a favorable IVIG effect on the rates of patients with sustained progression. In patients with PPMS, this IVIG effect reached significance (P=0.036). Other secondary endpoints did not show significant differences between treatment groups. Eighteen patients with PPMS and 102 patients with SPMS withdrew from the study for various reasons. Treatment was generally well tolerated. It was concluded that monthly IVIG infusion could delay progression of disease in patients with PPMS, and that there was a trend in favour of IVIG treatment in patients with SPMS.

Immunomodulating drugs in multiple sclerosis: compliance, satisfaction and adverse effects evaluation in a German multiple sclerosis population.

OBJECTIVE: To assess the compliance, satisfaction and adverse effects of immunomodulating drugs in a German multiple sclerosis (MS) population. RESEARCH DESIGN AND METHODS: A standardised, anonymous questionnaire was sent to the 1985 members with MS of the Berlin section of the German Multiple Sclerosis Association. Patients were questioned with regards to sociodemographic data, MS-related topics, therapy, adverse effects and compliance. The response rate was 51.1%, from which 681 patients were selected who were experienced in therapy with interferon beta 1a or 1b or glatiramer acetate. RESULTS: Most participants were treated with beta-interferons and only one-third with glatiramer acetate. Patients were moderately satisfied with their medication. Approximately 75.5% of patients had used the medication for longer than 2 years, especially those with a relapsing-remitting course (RRMS). Around one-third of all participants had their immunomodulating drug changed, mostly only once. The main reasons for discontinuation of the therapy were adverse effects, physician's recommendation and lack of treatment effect. Mood-related adverse effects (e.g., depression), fever and pain were perceived as most disturbing. Regression analysis revealed that dependence on a wheelchair and a secondary progressive course predicted a low compliance to treatment. CONCLUSION: Treating MS is a challenge and to positively influence the course of the disease it is necessary to administer medication in a constant manner. Our data showed a moderate compliance and satisfaction with the immunomodulating medication. Adverse effects and perceived lack of treatment effect were reasons for discontinuation of therapy. To increase compliance and satisfaction with treatment, adequate information about MS, the therapeutic options, handling of medication, side-effects and their management are necessary. Additionally, realistic therapeutic aims should be discussed with the patients.

Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study.

An exploratory, prospective, open-label study of fumaric acid esters (FAE, Fumaderm(R)) was conducted in patients with relapsing-remitting multiple sclerosis (RRMS). The study consisted of the following four phases: 6-week baseline, 18-week treatment (target dose of 720 mg/day), 4-week washout, and a second 48-week treatment phase (target dose of 360 mg/day). Ten patients with an Expanded Disability Status Scale (EDSS) score of 2.0-6.0 and at least one gadolinium-enhancing (Gd+) lesion on T1-weighted magnetic resonance imaging (MRI) brain scans participated in the study. Safety was assessed by adverse events (AEs), blood chemistry/hematology, electrocardiogram, and urinalysis. The primary efficacy outcomes were number and volume of Gd+ lesions. Other clinical outcomes included EDSS score, ambulation index (AI), and nine-hole peg test (9-HPT). Effects of FAE on intracellular cytokine profiles, T-cell apoptosis, and soluble adhesion molecules were also assessed. Three patients withdrew during the first 3 weeks of the study because of side effects, non-compliance, and follow-up loss. The most common AEs were gastrointestinal symptoms and flushing; all AEs were reported as mild and reversible. FAE produced significant reductions from baseline in number (P < 0.05) and volume (P < 0.01) of Gd+ lesions after 18 weeks of treatment; this effect persisted during the second treatment phase at half the target dose after the 4-week washout period. EDSS scores, AI, and 9-HPT remained stable or slightly improved from baseline in all patients. Measures of T-cell function demonstrated alterations in cytokines and circulating tumor necrosis factor. The results of this exploratory study suggest that further studies of FAE in patients with MS are warranted.

Repeat intrathecal triamcinolone acetonide application is beneficial in progressive MS patients.

Available immunomodulatory and conventional steroid treatment regimens provide a limited symptomatic benefit for patients with progressive multiple sclerosis (MS). We performed an open trial on the short-term efficacy of repeated intrathecal application of the sustained release steroid triamcinolone acetonide (TCA) in 27 progressive MS patients. Six TCA administrations, performed every third day, reduced the Expanded Disability Status Scale (EDSS) score [initial: 5.4+/-1.3, 3-7.5 (mean+/-SD, range); end: 4.9+/-1.1; 2.5-6.5; P<0.001] and significantly increased the walking distance and speed in particular after the fourth TCA injection. Concomitantly serially determined cerebrospinal fluid (CSF) markers of cell injury, neuron-specific enolase, total tau-protein, S-100, and beta-amyloid did not significantly change within the interval of TCA treatment. No serious side effects appeared. We conclude that repeat intrathecal injection of 40 mg TCA provides a substantial benefit in progressive MS patients with predominant spinal symptoms and does not alter CSF markers of neuronal cell injury.

MSBase: an international, online registry and platform for collaborative outcomes research in multiple sclerosis.

Observational cohort studies are a powerful tool to assess the long-term outcome in chronic diseases. This study design has been utilized in local and regional outcome studies in multiple sclerosis (MS) and has yielded invaluable epidemiological information. The World Wide Web now provides an excellent opportunity for an international, collaborative cohort study of MS outcomes. A web platform--MSBase--has been designed to collect prospective data on patients with MS. It is purely observational, enabling participating neurologists to contribute data on diagnosis, treatment and progress, to review anonymous aggregate data and to benchmark their patient population against other patient subsets or the entire dataset. MSBase facilitates collaborative research by allowing the online creation of investigator-initiated regional, national and international substudies. The registry aims to answer epidemiological questions that can only be addressed by prospective assessments of large patient cohorts. The registry is funded through the independent MSBase Foundation, and governed by an International Scientific Advisory Board. The MSBase Foundation commenced operations in July 2004 and since then, 22 neurologists from 11 countries have joined MSBase and are contributing 2400 patients to the total data pool.

[Quality of life in patients with remitting-relapsing multiple sclerosis in Germany]. / Lebensqualität bei Patienten mit schubförmiger MS in Deutschland.

The concept of health-related quality of life (QoL) includes physical, psychological,and social aspects. This pertains to consequences of chronic diseases and their therapies beyond biological or pharmacological relations. A considerable amount of literature concerning QoL has been published with regard to neurological and non-neurological entities. This study summarizes data from a study in 717 persons with remitting-relapsing multiple sclerosis (MS). Of them,576 could be reevaluated longitudinally after 1 year of treatment with interferon-beta 1a (44 microg subcutaneous Rebif once weekly). Compared to populations of healthy controls or other patients, considerable reductions in the eight subscales and both physical and emotional sum scales of the German version of the short form of the Rand Health Questionnaire (SF-36) questionnaire were assessed. These reductions were even more pronounced in persons with gait impairments. Most SF-36 scales only modestly correlated to physical disability. This indicates that QoL as reported by patients does not depend solely on the physical symptoms of MS. Most findings remained stable for the study population as a whole during 1 year of therapy, while statistically significant improvements were found in clinical responders as defined in this study (relapse-free, physically stable, stable or improved in physician's judgement). Side effects of therapy were not reflected in lower QoL scale values. Implications of findings for future concepts in MS therapy are discussed.

A null mutation within the ciliary neurotrophic factor (CNTF)-gene: implications for susceptibility and disease severity in patients with multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Impaired remyelination and axonal degeneration may account for progressive disability in MS patients. As ciliary neurotrophic factor (CNTF) takes part in myelogenesis, we examined the frequency of a CNTF-null mutation in 349 MS patients with respect to their clinical presentation and in comparison with 434 healthy controls. Similar genotype frequencies for the CNTF mutation were obtained in MS patients (genotype 0101=74.8%, 0102=22.3%, 0202=2.9%) and controls (genotype 0101=71.7%, 0102=26.5%, 0202=1.8%) even after stratification for the HLA-DRB1*15 allele. In addition, there was no significant correlation of CNTF genotypes to age at onset, course or severity of the disease. We therefore conclude, that the requirement for CNTF in myelogenesis or cell survival may be bypassed by a second ligand or redundancy of functional activity of other neurotrophic factors.

Multiple sclerosis: modulation of apoptosis susceptibility by glatiramer acetate.

OBJECTIVES: We investigated whether therapy of multiple sclerosis (MS) with glatiramer acetate (GA) involves the modulation of programmed cell death (apoptosis) in disease-relevant T-helper lymphocytes. MATERIAL AND METHODS: Blood was drawn from 15 relapsing-remitting MS patients both before (baseline) as well as 6, 12, and 18 weeks after GA therapy and from 15 healthy controls. Detection of apoptosis was performed in response to in vitro stimulation with GA, myelin basic protein or medium alone. RESULTS: T-helper lymphocytes from untreated MS patients displayed an overall increased apoptosis susceptibility in vitro, compared to controls. During subsequent GA therapy, apoptosis vulnerability of these T cells in MS patients significantly declined under the initial baseline before treatment, and was finally equal in treated patients and controls. GA itself had no direct apoptosis-modulatory properties in vitro. CONCLUSION: Our findings indicate that therapy of multiple sclerosis with glatiramer acetate presumably involves the compensation of altered apoptosis in T-helper lymphocytes.

Problems reported by elderly patients with multiple sclerosis.

Multiple sclerosis (MS) is one of the most common organic neurological diseases of the central nervous system. Because of improved therapies, nurses are confronted with elderly MS patients, but little is known about the specific problems of these patients. This survey analyzed problems in elderly MS patients. Fifty-three MS patients (44 female, 9 male; average age 73 years, average course of MS 25.3 years) from the Berlin Section of the German Multiple Sclerosis Association were evaluated by using a standardized questionnaire, considering social situation, daily problems, disease course, and disabilities, and by using the expanded disability status scale (EDSS). Elderly MS patients reported impaired mobility and inability to use public transportation; about 96% presented EDSS scores above 6.0. Nearly 50% complained about spasticity and pain due to spasticity. More than 70% suffered from bladder dysfunction. Problems with sleep and fatigue were present in less than 20%, but interrupted sleep was common. Selfcare impairments were reported by 50%-75% of the patients, and most of them required professional help. Depressive moods and thoughts about committing suicide were mentioned by more than 30% of the patients. Elderly MS patients experience physical and psychosocial impairments. Healthcare professionals should consider increasing independence and avoiding nursing home admissions in the management of elderly MS patients.

[An extreme case of environmental neurosis]. / Ein Fall einter "Umweltneurose" skurrilen Ausmasses.

A 64 year old female patient was diagnosed with scleroderma and has been bed-ridden for 25 years. She wears no clothing whatsoever on the grounds of an intolerance to textiles, and has spent the last eight years uninterruptedly in bed in a construction of kitchen paper towels and rubber bed sheets. A somatic disease has been be ruled out and cenesthesic schizophrenia diagnosed. As differential diagnoses, somatization, somatiform disorders and hypochondria were considered. The patient refused any psychiatric treatment.

The interferon gene cluster: a candidate region for MS predisposition? Multiple Sclerosis Study Group.

The clinical benefits of interferon (IFN) beta therapy in some multiple sclerosis (MS) patients are still unexplained, raising the question whether polymorphism within the IFNB gene itself would provide an explanation. Screening the IFNB gene by single strand conformation polymorphism (SSCP) analysis and sequencing, a single nucleotide polymorphism was identified. Both alleles were distributed with similar frequencies in MS patients and controls. Significant linkage disequilibrium (LD) between the IFN allele [153C] and allele [02] of the previously analyzed IFNA microsatellite (Epplen et al. Ann Neurol 1997; 41: 341-352) was observed in MS patients only, indicating a disease related haplotype. On the other hand an increased risk (RR = 12.41; Pc < 8 x 10(-5)) was observed for allele [07]. Hence the study was extended to neighbouring genes. Functionally relevant polymorphisms, i.e., premature stop codons in the IFNA10 [Cys20Stop] and IFNA17 [58Stop] genes and an aminoacid (aa) substitution [ile 184Arg] in the IFNA17 gene were analyzed. Patients carrying a non-functional IFNA17 allele bear an increased risk to develop MS (RR = 25.68; Pc < 0.06). In addition, LD analysis between IFNA10 [Cys20Stop], IFNA17 [58Stop] and the IFNA microsatellite alleles provides evidence for IFNA14, IFNA16 or IFNA5 as additional, most likely candidate genes. The present study excludes the IFNB gene as a candidate for MS predisposition but provides first evidence for predisposing IFNA genes.

[Promoting remyelination as a future therapeutic principle in multiple sclerosis?]. / Remyelinisierungsförderung als zukünftiges Therapieprinzip der Multiplen Sklerose?

Multiple sclerosis (MS), the most common neurological autoimmune disorder diagnosed in young adults, is characterised by the repeated occurrence of demyelinating lesions within the central nervous system (CNS). Promotion of remyelination in the brain and spinal cord constitutes a potential strategy for therapeutic intervention in MS and other demyelinating diseases. Three different principles are known to promote remyelination in the CNS of different animal models: Application of growth factors, transplantation of myelin-forming cells and intravenous immunoglobulin (IVIg) therapy. However, the systemic application of growth factors could be limited by effects on unaffected tissue. For successful transplantation we still have the problem of homologous cells not tolerated by a immunological different organism. Currently the required combination of growth factors needed to cultivate human homologous cells is not known, so that cells suitable for transplantation are still not available. Nevertheless, there is increasing evidence for beneficial effects of IVIg therapy on the promotion of remyelination in humans. In this review we summarise recent findings on the regulation of myelin sheath development and oligodendrocyte differentiation, and discuss the presented strategies in the context of possible clinical application for the therapy of MS.